Abstract
BackgroundElderly patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, but they are still underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy are lacking. Importantly, immunosenescence in elderly patients might interfere with activities of immune-modulating drugs such as PD-1/PD-L1 inhibitors. Thus, there is an urgent need to assess safety and efficacy of such inhibitors in this group.Methods/designThis prospective, open label, treatment stratified, randomized phase II study will enroll 200 patients with stage IV NSCLC amenable at least to single-agent chemotherapy (CT). Eligible patients must be aged 70 years or older and/or “frail” (Charlson Comorbidity Index > 1) or have a restricted performance status (Eastern Cooperative Oncology Group, ECOG > 1).Patients are stratified according to modified Cancer and Age Research Group (CARG) score: “fit” patients are allocated to combination CT (carboplatin/nab-paclitaxel) and “less fit” patients receive single-agent CT (gemcitabine or vinorelbine). After allocation to strata, patients are randomized 1:1 to receive either four cycles of CT or two cycles of CT followed by two cycles of durvalumab and subsequent maintenance treatment with durvalumab every 4 weeks.The primary endpoint is the rate of treatment-related grade III/IV adverse events (Common Terminology Criteria for Adverse Events (CTCAE) V4.03). As secondary endpoints, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, response rate (RR), overall survival (OS), descriptive subgroup analyses according to PD-L1 expression, and quality of life are addressed. Geriatric screening assessments and functional tests will be performed to complete the phenotyping of a potential “frail” and “elderly” patient cohort. The trial is accompanied by a biomaterial repository to explore potential biomarkers.DiscussionThe DURATION trial will prospectively investigate the safety and tolerability of anti-PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this cohort of patients.Trial registrationClinicalTrials.gov, NCT03345810; initially registered on 17 November 2017.Eudra-CT, 2016–003963-20; initially registered on 3 January 2017.
Highlights
Patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, but they are still underrepresented in clinical trials
According to the results presented at American Society of Clinical Oncology (ASCO) 2015 by Rizvi et al, it is assumed that the probability for a CTC grade III/IV toxicity for patients from the pooled experimental arms B + C receiving durvalumab amounts to PB + C = 0.18 [24]
Lung cancer is the most common cause of cancerrelated death worldwide and it is predominantly a disease of the elderly, with about 50% of patients diagnosed aged 70 years or older and with about 14% of these being older than 80 years [2]
Summary
Lung cancer is the most common cause of cancerrelated death worldwide and it is predominantly a disease of the elderly, with about 50% of patients diagnosed aged 70 years or older and with about 14% of these being older than 80 years [2]. The combination chemotherapy applied in the DURATION trial consists of a combination of nab-paclitaxel with carboplatin as inferred from clinical trials and retrospective analyses that demonstrated superiority of carboplatin/nab-paclitaxel over carboplatin/paclitaxel with respect to efficacy and safety in elderly patients [25, 31] Both patient groups treated with either single-agent or doublet chemotherapy will be subjected to randomization for treatment with the PD-L1 inhibitor durvalumab. Given the putatively lower risk of developing autoimmunemediated toxicities with PD-L1 targeting agents, the use of durvalumab, a selective, high-affinity, human IgG1 monoclonal anti-PD-L1 antibody [38,39,40], is expected to be more suitable for treatment of a more vulnerable patient group such as old or frail NSCLC patients that are included in the DURATION trial. The approximate end of recruitment will be in December 2020
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